Abstract
Secretion of multifunctional estrogen and its receptor has been widely considered as the reason for markedly higher frequency of heart disease in men than in women. 17β-Estradiol (E2), for instance, has been reported to prevent development of cardiac apoptosis via activation of estrogen receptors (ERs). In addition, protein phosphatase such as protein phosphatase 1 (PP1) and calcineurin (PP2B) are also involved in cardiac hypertrophy and cell apoptosis signaling. However, the mechanism by which E2/ERβ suppresses apoptosis is not fully understood, and the role of protein phosphatase in E2/ERβ action also needs further investigation. In this study, we observed that E2/ERβ inhibited isoproterenol (ISO)-induced myocardial cell apoptosis, cytochrome c release and downstream apoptotic markers. Moreover, we found that E2/ERβ blocks ISO-induced apoptosis in H9c2 cells through the enhancement of calcineurin protein degradation through PI3K/Akt/MDM2 signaling pathway. Our results suggest that supplementation with estrogen and/or overexpression of estrogen receptor β gene may prove to be effective means to treat stress-induced myocardial damage.
Highlights
According to the statistics from the World Health Organization, heart disease is the most common cause of disease-related death worldwide and is markedly more common in men than in women.heart disease risk and incidence surges sharply in women with increasing age [1]
Cardiomyocyte apoptosis are observed to be elevated in severe hypertrophic conditions and intensifies the adverse outcomes of LV hypertrophy associated in terms of reduction in the cardiac contraction and function [30]
Previous reports indicated that activation of β-adrenergic receptor (β-AR) by elevated plasma NE and ISO causes serious cardiac cell apoptosis in vivo and in vitro [31,32,33]
Summary
According to the statistics from the World Health Organization, heart disease is the most common cause of disease-related death worldwide and is markedly more common in men than in women. E2 is the most abundant and most active estrogen in women Both ER α and ER β exist in the cardiomyocytes and E2 has been known to prevent development of heart disease via ER β [2,3,4,5,6]. Previous reports show that estrogen is involved in modulating calcium-handling proteins, heart function, and blood flow; it reduces vascular inflammation and arrhythmias; prevents cardiac hypertrophy and myocardial cell apoptosis [13,14,15]. Protein phosphatase, such as PP2B (calcineurin) and type 1 phosphatase (PP1) are involved in cardiac hypertrophy, apoptosis, calcium influx, and heart failure. In this study we established a Tet-on ER β system in H9c2 myocardial cells and neonatal rat ventricular myocyte (NRVM) cells, to identify if E2/ER β inhibit ISO-induced myocardial cell apoptosis effects, and further investigated the roles of phosphatases (PP1 and PP2B) in the effect of E2/ER β
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